Endurance exercise has emerged in recent years as a potent intervention capable of improving a wide variety of health parameters in humans and in vertebrate models. Although much has been learned about physiological responses to exercise training in vertebrates, the genetic components necessary for these responses are still not well understood. With this in mind, we have developed a novel endurance exercise model in a genetically tractable research organism, the fruit fly. Flies of multiple genotypes respond to a program of endurance exercise by improving climbing ability and cardiac stress resistance, as well as increasing mitochondrial activity, suggesting that exercise produces similar effects in invertebrates as in vertebrates. In order to fully establish the utility of this model system, however, it will first be necessary to more fully characterize the similarities and differences between the exercise response in flies and in vertebrates. Here, we propose to establish the relevance of flies as an exercise model by characterizing a variety of physiological responses to exercise in the fly model. Secondly, we propose to establish conservation of genetic pathways involved in these responses by testing candidate genes known to be important in regulating vertebrate physiology for their effects on the exercise response of the fly. Once the relevance of flies as an exercise model is established, the power of fly genetics can be used to uncover novel conserved genetic factors capable of regulating or mimicking the exercise response in vertebrates. PUBLIC HEALTH RELEVANCE: Understanding genetic mechanisms of exercise physiology is relevant to the mission of the National Institutes of Health and the National Heart Lung and Blood Institute because the identification of key genetic components of the response will allow design of treatments and prevention programs for degenerative muscular diseases and age-related decline in muscular function.